2-imidazolidine substituted quinoxaline-1,4-dioxides and intermediates therefor

ABSTRACT

WHEREIN X is a 6- or a 7-position substituent and is hydrogen, chloro, bromo, fluoro, methyl, methoxy and trifluoromethyl; Y is O, S and NR1 wherein R1 is hydrogen and lower alkyl; A is alkylene of from two to five carbon atoms which places at least two carbon atoms between the N and Y or Z atoms to which it is attached; R2 is lower alkyl; Z is chloro and bromo; THE NON-TOXIC ACID ADDITION SALTS OF THOSE COMPOUNDS WHEREIN Y is -NR1; and method for their preparation are described. All compounds of formulae I and II are useful as antibacterial agents. Compounds of formulae II are valuable intermediates for further synthesis.   The 2-heterocyclic- and 2-(N-( omega haloalkyl)carbamyl)substituted quinoxaline-1,4-dioxides having formulae I and II, respectively:

United States Patent [1 1 Abu El-Haj 1 Z-IMIDAZOLIDINE SUBSTITUTED QUINOXALINEJA-DIOXIDES AND INTERMEDHATES THEREFOR [75] Inventor: Marwan J. Abu El-Haj, Gales Ferry,

Conn.

[73] Assignee: Pfizer llnc., New York, NY.

[22] Filed: Oct. 10, 1973 [21] Appl. N0.: 405,114

Related US. Application Data [60] Continuation of Ser. No. 207,534, Dec. 13, 1971, abandoned, which is a division of Ser. No. 20,842, March 18, 1970, Pat. No. 3,671,521.

[52] US. Cl. 260/250 Q, 260/2564 F, 424/250 [51] Int. Cl C07d 51/78 [58] Field of Search 260/250 Q, 256.4 F, 256.4 H

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 2,107,301 9/1971 Germany 260/2564 2.111.710 3/1971 Germany 260/250 Q 2,228,802 12/1972 Germany 260/250 Q Primary E.\'aminerDonald G. Daus Assistant ExaminerRa1ph D. McCloud Attorney, Agent, or Firm-Connolly and Hutz [57] ABSTRACT The Z-heterocyclicand 2-[N-(w-haloalkyl)carbamy1]- Mar. 11, 1975 substituted quinoxaline-l,4-dioxides having formulae 1 and II, respectively:

R is lower alkyl; Z is chloro and bromo;

the non-toxic acid addition salts of those compounds wherein Y is NR,; and method for their preparation are described. All compounds of formulae 1 and 11 are useful as antibacterial agents. Compounds of formulae II are valuable intermediates for further synthesis.

7 Claims, N0 Drawings Z-IMIDAZOLIDINE SUBSTITUTED QUINOXALINE-lA-DIQXIDES AND INTERMEDIATES THEREFOR CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of application Ser. No. 207,534, filed Dec. 13, 1971, and now abandoned, which in turn, is a division of application Ser. No. 20,842 filed Mar. 18, 1970 and now US. Pat. No. 3,671,521.

BACKGROUND OF THE INVENTION This invention relates to novel 2-heterocyclic substituted quinoxaline-1,4-dioxides which are useful antibacterial agents.

The unceasing quest for antibacterial agents has resulted in the production of a wide variety of structural types of organic compounds, including many derivatives of quinoxalinel ,4,-dioxides. A series of 2-methyl- 3-amidinoquinoxaline-l,4-dioxides having antibacterial activity is described in Belgian Pat. No. 721,727, published Apr. 2 1969. A variety of 2- quinoxalinecarboxamide-l,4-dioxides is also described in the recent patent literature.

French Pat. No. M3717, granted Jan. 3, 1966, generically discloses Z-quinoxalinecarboxamide-1,4-dioxides in which the carboxamide group may be substituted with an alkyl, substituted alkyl, aryl, cycloalkyl, aralkyl or cycloalkylalkyl group; or may form a heterocyclic amide, e.g., a piperidide. They are reported to be of use in human therapy as antitubercular, antibacterial, anticancer, antivirus and antiprotozoal agents.

Belgian Pat. No. 697,976, granted Nov. 3, 1967, describes a variety of N-substituted derivatives of 3- methyl-2-quinoxalinecarboxamide-1,4-dioxide in which the N-substituent is phenyl, substituted phenyl, dodecyl or ethyl. Also disclosed are cyclic amides, e.g., pyrrolidide and piperidide. They are said to be of value as intermediates for the preparation of vegetation protection agents and pharmaceutical agents. BelgianPat. Nos. 721,724; 721,725; 721,726; and 721,728, published Apr. 2, 1969, describe a variety of N-substituted 3-methyl-2-quinoxalinecarboxamide-1,4-dioxide derivatives wherein the N substituent is hydroxyalkyl, lower alkoxyalkyl, carbalkoxyalkyl, monoalkylaminoalkyl or di(alkyl)aminoalkyl which are useful as antibacterial agents.

SUMMARY OF THE INVENTION It has now been found that novel Z-heterocyclic substituted quinoxaline-1,4dioxides and intermediates therefor having formulae I and II, respectively:

wherein X is a 6-or a 7-position substituent and is selected from the group consisting of hydrogen, chloro, bromo, fluoro, methyl, methoxy and trifluoromethyl;

Z is selected from the group consisting of chloro and bromo;

Y is selected from the group consisting of O, S and NR, wherein R is selected from the group consisting of hydrogen and lower alkyl;

A is alkylene of from two to five carbon atoms which places at least two carbon atoms between the N and Y or Z atoms to which it is attached;

R is lower alkyl;

and the non-toxic acid addition salts of those compounds wherein Y is -NR are effective broadspectrum antibacterial agents in vitro. Still further, the compounds, of formula II are useful as intermediates for the synthesis of other antibacterial agents as is described below.

By the term lower alkyl as used herein is meant those alkyl groups containing from one to four carbon atoms since the compounds bearing such groups are conveniently prepared from easily available reactants.

The substituents on the fused benzene moiety of the above compounds can vary widely. For example, at least one of the following substituents can be present: hydrogen, lower alkyl, lower alkoxy, chloro, bromo, fluoro, trifluoromethyl, di(lower alkyl)amino, amino, carboxy, carbamyl, carbo(lower alkoxy), lower alkylmercapto. lower alkylsulfoxy, lower alkylsulfonyl, sulfonamido and N,N-di(lower alkyl)sulfonamido. The favored positions on the fused benzene ring are the 6- and the 7-positions. Of special interest for these positions are at least one of the following substituents hydrogen, methyl, chloro, fluoro and methoxy. A single substituent, that is, a 6- or 7-substituent, is usually held in greater favor than is a 6,7-disubstituted derivative for reasons of economy as regards the reactants used. The preferred substituents, for reasons of economy and/or their favorable effect upon activity, are hydrogen, chloro and fluoro. Nitro, hydroxy and mercapto groups are not desirable substituents since they react with difficulty in the preferred process for making these novel compounds and/or result in formation of undesired products and poor yields.

Unique among the compounds of this invention by reason of their outstanding broad-spectrum activity are those compounds of formula I where Y is O, NH or N(lower alkyl); X is hydrogen or chloro, and A is ethylene or trimethylene.

It is noted that alkylene groups having more than five carbon atoms and which place from two to five carbon atoms in the heterocyclic ring between the two hetero atoms to which they are attached are also operative in this invention.

DETAILED SUMMARY OF THE INVENTION The novel compounds of this invention of formulae I and Ii above are conveniently prepared by reaction, in the presence of a base, of the appropriate benzofuroxan with a methylene-activated reactant of formulae III or IV, respectively (Method A):

III

5 wherein A, Y and Z are as defined above.

ture of solvents, which serves to dissolve at least the reactants and which does not enter into adverse reactions with the reactants or products. Appropriate solvents are ethers such as diethylether, diisopropylether, dioxane, tetrahydrofuran, dimethylethers of ethylene glycol and diethyleneglycol; alcohols especially the lower molecular weight alcohols having up to four carbon atoms; N,N-dimethylformamide, organic amines, benzene, toluene, xylene, acetonitrile, halogenated hydrocarbons such as chloroform, methylene chloride, and mixtures of these solvents.

The reaction is normally conducted over the temperature range of from about C. to about 100 C. and preferably from about 30 C. to about 100 C. Higher temperatures can be used but appear to offer no advantage and may in certain cases cause decomposition. The reaction period, as expected, depends not only upon the temperature but also upon the reactants and particularly upon the base used. For a given set of reactants, the higher the reaction temperature, the shorter the reaction period; the lower the reaction temperature, the longer the reaction period. In general, the reaction is conducted in a solvent system at reflux temperature for a period of up to 4 hours followed by standing at room temperature for several hours, e.g., overnight.

A wide variety of bases are operative in the reaction of benzofuroxan-methylene-activated reactant process of this invention such as, forexample, organic amines, ammonia, alkali metal hydroxides, alkali metal hydrides and alkali metal alkoxides. Representative of such bases are ammonia, primary amines such as methylamine, n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethylamine, octylamine; secondary amines such as diethylamine, dipropylamine, methyl-n-butylamine, pyrrolidine, morpholine, piperidine, pyrrole, pyrroline, N- methylaniline, N-methylbenzylamine, pyrimidine; tertiary amines such as triethylamine, trimethylamine, N,N-dimethylaniline, N-methylpyrrolidine, 1,2- dimethyl-l ,4,5,6-tetrahydropyrimidine, N- methylmorpholine and l,5-diazabicyclo[4,3,0]-5- nonene; sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, and sodium hydride. The preferred bases are the alkali metal hydroxides and primary alkylamines since they tend to minimize the reaction period relative to that required by other bases and are productive of satisfactory yields of the desired product.

The base itself, if liquid at the reaction temperature, can also be used as solvent. This provision, as those skilled in the art will recognize, limits the use of bases as solvents to organic amines and ammonium hydroxide.

' The amount of base required is not critical but can vary widely, e.g., from a trace or catalytic amount of base, that is, from about 0.001 percent by weight, based on the benzofuroxan reactant present, to even molar excess amounts as occurs when the base is used as solvent. In general, optimum amounts range from about 0.1 percent by weight to about equimolar amounts based on the benzofuroxan used. As will be readily appreciated, the optimum proportion of base will vary with the nature of the particular reactants employed, as well as specific reaction conditions. Accordingly, the optimum proportion of base is most conveniently established by routine experimentation using small scale laboratory reactions.

The molar ratio of reactants, that is, of the benzofuroxan and the methylene-activated reactant, is not critical but can varywidely, e.g., from equimolar proportions to a large excess of either reactant. They are, in general, reacted in equimolar proportions. As a practical measure when using a readily available methylene activated reactant, e.g., 2-acetonylthiazoline, an excess of the reagent is used to ensure as complete a conversion of the benzofuroxan to the desired product as is possible. Further, the excess methylene-activated reactant can also serve as solvent.

The order of addition of reactants is not critical to the success of this process. They can be added all at once along with the base or the base can be added to a mixture of the benzofuroxan and methylene-activated reactant. This latter method is advantageous in the case of exothermic reactions since it facilitates temperature control apparently by regulating the rate of reaction. In the case of such exothermic reactions, the use of an appropriate solvent also contributes to temperature control. As alternatives to the above methods of addition of reactants, either reactant can be added to the other in the presence of the proper base, or the reactants can be added simultaneously to the base.

Compounds of formula II, produced by the reaction of a benzofuroxan with a compound of formula IV, serve as precursors for formula I compounds (Y 0 and R methyl) as those skilled in the art will recognize. The conversion of formula II compounds to those of formula I (wherein Y is 0 and R is methyl) is, in fact, the preferred route to such compounds of formula I.

Utilization of compounds of formula IV in Method A, depending upon the reaction conditions employed, notably the amount of base, produces products of formula I (Y 0 and R methyl) or of formula II. The use of up to 0.25 mole of base per mole of benzofuroxan reactant produces compounds of formula II as the principal product. The use of larger amounts of base produces compounds offormula I (Y 0 and R methyl) as the major product.

Formula II compounds, N-(chloroalkyl)- and N- (bromoalkyl)-3 -methyl-2-quinoxalinecarboxamidel,4-dioxides, can be cyclized directly to compounds of formula I without isolation. Alternatively, they can be isolated by known methods as described herein. The bromo derivatives cyclize with greater ease than do the corresponding chloro derivatives. When isolation of the N-(bromoalkyl)-3-methyl-2-quinoxalinecarboxamide-l,4-dioxide is desired the minimal amount of base, not over 0.25 mole per mole of benzofuroxan reactant, is used. Additionally, the temperature is desirably held below about 40 C.

Cyclization of formula II compounds is readily accomplish'ed by treating them with at least one molar proportion of a base such as those enumerated above. In actual practice an excess of base, preferably a molar excess is used to ensure as rapid and complete cyclization as possible. The cyclization is carried out at a temperature of about 0 C. to about 50 C. and preferably at a temperature of from about 20 C. to about 35 C. for periods of up to 24 hours. The reaction period, of course, depends upon the reaction temperature, lower temperatures requiring longer reaction periods than do higher temperatures. In general, reaction periods of from about four to about twenty hours are satisfactory.

Alternatively, the preparation of compounds of formula I wherein Y is 0 and R is methyl is readily achieved by a simpler and more convenient process of broad applicability (Method B) described below.

Method B comprises reacting the appropriate ben zofuroxan with an appropriate chloro or bromoalkylamine of formula V:

wherein A and Z are as previously defined and m is 0 or 1 and diketene (ketene dimer). This is the preferred process since it utilizes readily available materials, is simple to carry out, and productive of satisfactory yields of the desired product of formula I (Y 0, R methyl) or of formula II depending upon the reaction conditions. The bromoor chloroalkylamine can be used as such or as the corresponding hydrobromide or hyrdochloride salt. The salts are, from a practical standpoint, frequently favored over the free base forms because of their better stability and ease of handling.

The reaction with the benzofuroxan reactant is most generally conducted in the presence of a base as catalyst. An excess of the bromo-or chloroalkylamine reactant, free base form, can, of course, be used as the base. However, other bases, such as those enumerated above in Method A are more efficient and more economical to use.

Here also, as in Method A and as noted above, the amount of base used determines whether the product is of formula I or formula II. The reaction is usually conducted in a suitable solvent system at a temperature of from about 0 C. to about 100 C. as is described for Method A.

The order of addition of reactants is not critical to the success of this process. The reaction can be conducted by simultaneous or stepwise addition of the various reactants including the excess amine or separte base as catalyst.

From a practical standpoint in order to achieve maximum yield of the desired quinoxaline-l,4-dioxide compound of formulae I or II, it is advantageous to react the diketene and amine containing reactant together in an appropriate solvent system for a brief period before adding the benzofuroxan. A preferred method comprises adding a solution of the desired amine in a reaction-inert solvent to at least an equimolar solution of diketene in the same or other reaction-inert solvent which is miscible with the amine solvent at a temperature of from about 0 C. to about 30 C. The mixture is then treated immediately with the catalyst and benzofuroxan reactant by dissolving this last reactant into the amine-diketene reaction mixture. The temperature of this phase of the reaction is not critical but can range up to about 100 C. In most instances, the temperature of this phase is kept below about 60 C. and is frequently run at room temperature for periods of up to 24 hours. In most instances, the reaction mixture is allowed to stand at room temperature for several hours, e.g., overnight.

Still a further procedure (Method C) comprises reacting the appropriate benzofuroxan with a preformed enamine of the ketone reactant of formula III or IV. A detailed review of the preparation and reactions of ma mines is presented by Szmuszkovicz, Advances in Organic Chemistry, Volume 4, pages 1-113, Interscience Publishers, New York (1963). Enamines are most conveniently prepared by the reaction of a ketone with a secondary amine, such as morpholine, pyrrolidine, pipieridine, N-methyl-N-cyclohexylamine, or di(lower alkyl)amines such as dimethylamine, diethylamine and di(n-butyl)-amines as is reported by Szmuszkovicz. Ammonia and primary amines can, of course, also be used. However, enamine formation via secondary amines is preferred because of the ease of preparation of such enamines.

The reaction comprises adding the enamine to a solution of the appropriate benzofuroxan in a suitable reaction-inert solvent such as those cited above at a temperature of from about 0 C. to about 100 C. and preferably at a temperature of from about 20 C. to about C. The products are recovered by evaporation of the solvent and are purified by recrystallization from a suitable solvent.

Compounds of formula I wherein Y is NR or S are also prepared by the reaction of an X-substituted-Z- cyano-3-R -substituted quinoxaline-1,4-dioxide with the appropriate alkylenediamine tosylate (H NANHR C H SO H) or thioalkylamine (H NASH), respectively, according to known procedures. Alternatively, the X-substituted-2-cyano-3- R -substituted quinoxaline-l,4-dioxide is converted to an imido ether hydrochloride which is then reacted with the appropriate alkylenediamine 'or thioalkylamine to provide the corresponding cyclic compound of formula I. As those skilled in the art will recognize, the above-mentioned reactions for preparing compounds of formula I wherein Y is NR lead to formation of the tosylate (p-toluenesulfonate) and hydrochloride salts of the cyclized product.

This method, as well as methods A and B above, produce both the 6-and 7-isomers of those compounds wherein X is other than hydrogen because of the existence of a dynamic, tautomeric equilibrium in the starting X-substituted benzofuroxan. The isomers, actually a mixture of isomers, are recovered by methods known to those skilled in the art. In many of the preparations disclosed herein a solid, often crystalline material, separates from the reaction mixture. The solid appears to consist predominantly of one of the isomers, which isomer can be purified by repeated recrystallization from a suitable solvent to a constant melting point. The other isomer, the one present in smaller amounts in the solid material, is the predominant product in the mother liquor. It can be recovered therefrom by methods known to those skilled in the art as, for example, by evaporation of the mother liquor and repeated crystallization of the residue to a product of constant melting point. Alternatively, the reaction mixture can be extracted with a suitable solvent, either before or after evaporation to dryness, and the extracted material which contains both isomers purified further by recrystallization.

The identification of the isomers has not been completed. Both isomers of a given compound, however, exhibit activity as antibacterial agents to a significant degree.

Acid addition salts of compounds of formula I wherein Y is NR are prepared by methods well known to those skilled in the art. A convenient method comprises dissolving the free base in a suitable solvent, e.g., acetone, water, a lower aliphatic alcohol (ethanol, isopropanol) containing the desired acid, or to which the desired acid is subsequently added. The salts are recovered by filtration, precipitation with a non-solvent, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization. In this manner, the sulphate, hydrochloride, hydrobromide, nitrate, phosphate, acetate, propionate, butyrate, citrate, gluconate, benzoate, pamoate. amsonate, the tartrate, 3-hydroxy- Z-naphthoate and the sulphosalicylate and other salts can be prepared.

The requisite 2-(oxoalkyl)-substituted heterocyclic compounds (formula III) are prepared from the corresponding 2-methyl substituted heterocyclic compounds. The process comprises reacting the lithio salt of the appropriate 2-methy1 substituted heterocyclic compound with a lower alkyl ester of the appropriate alkanoic acid; e.g., methyl or ethyl ester of acetic, propionic, butyric or isobutyric acid, with an acid halide of said alkanoic acid; e.g., acetyl, propionyl, butyryl or valeryl chloride (or bromide), or with a simple anhydride of said alkanoic acid; e.g., acetic, propionic or butyric anhydride.

The lithio salts of the 2-methyl substituted heterocyclic compounds are prepared by treating the appropriate 2-methyl heterocyclic compound with phenyl-, nbutyl-, or t-butyllithium in tetrahydrofuran at temperatures of from about 50 C. to about 80 C. as is described by Meyers, et al., in J. Am. Chem. Soc. 91, 7634 (1969). Addition of a lower alkyl ester or a simple anhydride or acid chloride to the tetrahydrofuran solution of the lithio salt at about --50 C to about 80 C. affords the acylated derivative: a 2-(oxoalkyl)substituted heterocyclic compound (formula III).

The precursor 2-methyl substituted heterocyclic compounds of formula VI VI wherein Y and A are as defined above and are prepared by known methods. Compounds wherein Y is NR are prepared by methods described in Elderfield, Heterocyclic Compounds," J. Wiley and Sons, Inc., New York (1957), Volume 5, pages 239-240; and Volume 6, page 248. Compounds wherein Y is O are prepared by procedure in Elderfield, Ibid., Volume 5, page 377, and Volume 6, page 334; and those wherein Y is S are described in Elderfield, lbid., Volume 5, page 679 and Volume 6, page 604. Typical procedures are exemplified herein.

The valuable products of this invention are remarkably effective in treating a wide variety of pathogenic microorganisms. They are, therefore, useful as industrial antimicrobials, forexample, in water treatment, slime-control, paint preservation and wood preservation, as well as for topical application purposes as disinfectants.

For in vitro use, e.g., for topical application, it will often be convenient to compound the selected product with a non-toxic carrier such as vegetable or mineral oil or an emollient cream. Similarly, they may be dissolved or dispersed in liquid carriers or solvents such as water, alcohol, glycols or mixtures thereof or other non-toxic inert media; that is, media which have no harmful effect on the active ingredient. For such purposes, it will generally be acceptable to employ concentrations of active ingredients of from about 0.01 percent to about 10 percent by weight based on total composition.

The following examples are given solely for the purpose of illustration.

ketene (8.4 g.) in chloroform ml.) at 0 C. and the mixture stirred rigorously. A solution of sodium hydroxide (4.1 g. in 20 ml. water) is then added to the stirred mixture over a period of 20 minutes at 0 C. The reaction mixture is then stirred at room temperature for 1 hour, the chloroform phase separated, dried with anhydrous sodium sulfate and evaporated to dryness to give a white solid: N-]2-bromoethyl)acetoacetamide.

The N-(2-bromoethyl)acetoacetamide (20.8 g.) and benzofuroxan (13.6 g.) are dissolved in ethanol (150 ml.) and ethylamine (16 ml.) slowly added to the solution while maintaining the temperature below 30 C. The reaction mixture is held at room temperature overnight then filtered to give 6.4 g. (26.1 percent yield) of the desired product; M.P. 211 C. Recrystallization from methanol-chloroform (l-l) raises the melting point to 217218 C.

Analysis: Calcd for C H N O %C, 58.77: %H, 4.52; %N, 17.14

Found: %C, 58.23; %H, 4.52; %N, 17.02.

EXAMPLE II N-(2-Chloroethyl)-3-Methyl-2-Quinoxalinecarboxamide- 1 ,4-Dioxide N-(2-chloroethyl)acetoacetamide (0.5 mole) is prepared by reacting 2-chloroethylamine hydrochloride (0.5 mole), diketene (0.5 mole) and sodium hydroxide (0.5 mole) in water (150 m1.)-chloroform (750 ml.) according to the procedure of Example I for making the corresponding, bromo derivative.

The N-(2-chloroethyl)acetoacetamide (0.5 mole) thus produced is dissolved in ethanol (800 ml.) and benzofuroxan (68 g., 0.5 mole) added. When solution is complete, n-propylamine (15 g., 0.18 mole) is slowly added to the solution while holding the temperature below 30 C. The reaction mixture is allowed to stand overnight at room temperature then filtered to give 19.1 g. of product. A second crop 23.8 g. is obtained by allowing the mixture to stand. Total yield: 42.9 g., 30.5 percent; M.P. -176 C. An analytical sample is obtained by recrystallizing the product from methanol; M.P. l76l77 C.

Analysis; Calcs for C l-l N O Cl; %C, 51.16; %H,

4.30: %N, 14.92; %Cl, 12.58 Found: %C, 50.88; %H, 4.29; %N, 14.95; %Cl,

EXAMPLE III 2-(2-0xazolin-2-yl)-3-Methylquinoxaline-1,4-

Dioxide A suspension of N-(2-chloroethyl)-3methyl-Z- quinoxalinecarboxamide-l,4-dioxide (36.0 g.) and 500 ml. of a 40 percent aqueous monomethylamine solution is stirred for twenty hours at room temperature. The N-(2-chloroethyl)-3-methyl-2- quinoxalinecarboxamide-l ,4-dioxide reactant dissolves slowly and the cyclized product crystallizes from the mixture. The reaction mixture is filtered, washed with water, then with acetone, and dried to give 26.7 g. of product; M.P. 217218 C. (83 percent yield).

EXAMPLE IV 2-( 5,6-Dihydro-4H-l ,3-Oxazin-2-yl)-3-Methyl Quinoxalinel ,4-Dioxide To a solution of diketene (4.2 g.) in chloroform (75 ml.) is added 3-bromopropylamine hydrobromide (10.4 g.) in water (20 ml.) at C. and the mixture thoroughly stirred. A solution of sodium hydroxide (2.0 g. in ml. water) is then added over a 20 hour period at 0 C. and the mixture stirred for an additional hour at room temperature. The chloroform phase is separated, dried with anhydrous sodium sulfate and evaporated to give N-(3-bromopropyl)acetoacetamide as a white solid.

The N-(3-bromopropyl)acetoacetamide is then added to a solution of benzofuroxan (6.8 g.) in ethanol (75 ml.) and an excess of ammonia gas passed into the solution (until the solution is saturated) while holding the temperature below 30 C. The reaction mixture is allowed to stand overnight at room temperature, then filtered to give the product: 2.0 g. (15.4 percent), M.P. 218 C. when recrystallized from methanol.

EXAMPLE V Following the procedure of Example I, the 2- hetero'cyclic substituted quinoxaline- 1 ,4-dioxides listed below are prepared from the appropriate benzofuroxan and w-bromo-(or chloro)alkylamine hydrobromide reactants. The 6- and 7-isomers are produced in each instance.

In this and subsequent tables. the A group listed is written in Such a manner that the left bond of the group is attached to the =N atom of the hctcrocyclic ring and the right bond of the group to the other hetcrozitom, in this Example. to 0.

EXAMPLE V1 2-(2-lmidazolin-2-yl )-3-Methylquinoxaline-l ,4-

Dioxide A. 2-Acetonylimidazoline (6.3 g., 0.05 mole) and benzofuroxan (8.3 g., 0.05 mole) are added to a 0.5 molar solution of sodium methoxide in methanol ml.) and the mixture refluxed for 3 hours. The solvent is reduced under reduced pressure and the residue crystallized from methanol-chloroform (1:1).

B. The enamine of 2-acetonylimidazoline and pyrrolidine (0.05 mole), prepared according to the procedure of Example X-C, and benzofuroxan (0.05 mole) in methanol (100 ml.) at 30 C. are stirred for 1 hour. The solution is then taken to dryness under reduced pressure and the residue recrystallized from methanolchloroform (1:1).

EXAMPLE VII 2-(2-Imidazolin-2-yl)-3-Methylquinoxaline-1,4-

Dioxide Tosylate A mixture of 2-cyano-3-methylquinoxaline-1,4- dioxide (10 g., 0.05 mole), ethylenediamine (3.3 g., 0.055 mole) and p-toluenesulfonic acid monohydrate (9.5 g., 0.05 mole) is heated at C. to C. for 8 hours during which time the evolution of ammonia is noted. The mixture is then cooled and recrystallized from methanol-chloroform.

The tosylate salt is converted to the base by treating the salt in water with aqueous sodium hydroxide (l0 1 1 percent excess) and extracting the cyclic amidine with ethyl acetate. The ethyl acetate extracts are dried (Na S and the'solvent evaporated to give the free base form of the title compound.

EXAMPLE VIII 2-[ 2-( l ,4,5 ,6-Tetrahydropyrimidin-2-yl) ]-3-Methyl- Quinoxaline-I ,4-Dioxide Hydrochloride EthyI-( 3methylquinoxaIine-Z-formimidate)- I ,4- dioxide hydrochloride (14.7 g., 0.05 mole) is added to a solution of trimethylenediamine (3.7 g., 0.05 mole) in ethanol (200 ml.) at 0 C., the mixture thoroughly stirred, then heated to reflux overnight. Evaporation of the mixture (under reduced pressure) to dryness gives the desired product.

Treatment of the product with a slight excess of 40 percent aqueous sodium hydroxide at 5 C. affords the free base which is extracted with ether. The ether solution is dried and evaporated to dryness to recover the free base form of the title compound.

EXAMPLE IX Following the procedures of Examples VI, VII and VIII, the cyclic amidine derivatives listed below are prepared from the appropriate benzofuroxan and 2- acetonyl substituted cyclic amidines (Example VI-A) or the preformed enamine of the Z-acetonyl substituted cyclic amidine (Example VI-B); or from the appropriate alkylenediamine and X-substituted-2-cyano-3- methylquinoxaIine-l,4-dioxide (Example VII), or the ethyIimido-ether hydrochloride of the 'X-substituted-Z- cyano-3-methylquinoxaline-1,4-dioxid (Example VIII). I

Repetition of the above procedures but substituting the above named reactants; i.e., Z-acetonyl substituted cyclic amidine or preformed enamine thereof, or X- substituted-2-cyano-3-methylquinoxalinel ,4-dioxide and ethyl-imido-ethers thereof; by the 2-(oxoalkyl) cyclic amidines of Preparation F (compounds of formula III wherein Y is NR as defined herein) or preformed enamine thereof, or by an X-substituted-2-cyano-3- lower alkyl-quinoxaline-l ,4-dioxide (Preparation G) or ethylimido-ether thereof (Preparation E), respectively, produces the corresponding products wherein the 2- methyl group is replaced by a 3-lower alkyl group.

EXAMPLE X 2-( Z-Thiazolin-Z-yl)-3-Methylquinoxaline-l ,4-

Dioxide A. Benzofuroxan (8.3 g., 0.05 mole) and 2-' acetonylthiazoline (7.2 g., 0.05 mole) are added to a 0.5 molar solution of sodium methoxide in methanol (100 ml.) and the mixture refluxed for three hours. The solvent is then removed by distillation in vacuo and the residue crystallized from methanolchloroform (1:1).

B. Repetition of the above procedure but using morpholine (4.3 g.) and benzene (300 ml.) in place of sodium methoxide and methanol produces the same product.

C. Use of Preformed Enamine. A mixture of thiophenefree benzene (300 ml.), pyrrolidine (4 mole equivalents) and 2-acetonylthiazoline (0.05 mole) is heated at reflux until one mole equivalent of water is collected in a Bidwell-Sterling moisture trap placed between the reaction flask and the condenser. The mixture is then evaporated to dryness in vacuo, care being taken to exclude moisture. The residue is triturated with methanol, cooled and filtered.

The enarnine is then added to a solution of benzofuroxan (0.05 mole) in methanol (100 ml.) at 30C., the mixture stirred for one hour, then taken to dryness in vacuo. The product is recrystallized from methanolchloroform. It is identical to the product of Method A above.

EXAMPLE XI The following compounds are prepared by the above method but using the appropriate substituted ben- X Method F CH OCH,

The 6 and the 7-isomers are produced in each instance.

EXAMPLE XII 2-[2-(5 ,6-Dihydro-4H-l ,3-Thiazin-2-yl)]-3- Methylquinoxaline-l ,4-Dioxide A mixture of 2-cyano-3-methylquinoxaline-l ,4- dioxide 10 g., 0.05 mole), 3-mercaptopropylamine hydrochloride (8.76 g., 0.053 mole) and absolute ethanol (50 ml.) is heated under reflux until ammonia is no longer evolved. The mixture is cooled to room temperature, poured into cold water (250 ml.) and made basic with potassium hydroxide (6N). The oil which separates is extracted with ether, the ether extract dried over anhydrous sodium sulfate and evaporated to dryness to give the product.

EXAMPLE XIII 2-( 2-Thiazolin-2-yl)-3-Methylquinoxaline-l ,4- Dioxide To a solution of 2'-mercaptoethylamine(2.27 g., 0.02 mole) in ethanol ml.) at 0 C. is added ethyl (3- methylquinoxaline-Z-formimidate)-l,4-dioxide (4.9 g., 0.02 mole). The mixture is stirred, heated to reflux overnight, then evaporated to dryness under reduced pressure to give the product.

EXAMPLE XIV The procedure of Example VI-A is repeated but using the appropriate 2-acetonyl substituted heterocyclic compound and the appropriate benzofuroxan reactant to produce compounds having the formula:

-Continued A A X Y A X Y A (CH2)5 a) a)2 CH,(CH3)CH2 -CH(CH3)CH,CH2CH2 H s -cH cH )c1-r cr-r- F S a)2 2 CHZCH(CHS) *CWQHQCWCWF 5 z 5) 2 a)z z S CH(CH;,)CH(CH- H, S -CH CH(CH )C- --CH(CH3)CH(CH- CH2C(CH;,), cH s CH(CH )CH(CH- Cl s CH CH(CH )C- OCH 3 S CH(CH3)CH(CH- OCH S CH2CH(CH;,)C- H s 3 EH C(CH H s C H(C H )CH PREPARATION B Cl S Cl S 2-Methyl Cyclic Amidines CF S -CH,C(Ct-t OCH S -CH(C H.-,)CH2 The followmg compounds are prepared according to H 5 f H S the procedure of Riebsomer, J. Am. Chem. Soc. 70, CH2CH2CH2CH(CH3) 1629 (19481 which comprises adding benzene to an Br 5 TCH(Cl-t )C(CH=. Cl S equimolar mixture of the appropriate alkylenediamine CHzCHzCHZCHCHa) gal-[ N A NHR and acetic acid and distilling the OCH S CH(CH3)C(CH3 H s enzene and by-product water through a packed fourfoot column. The benzene 15 returned to the reaction z 5) flask and heating continued at a temperature of from about 150 C. to about 220 C until one mole of water is collected. The product is then distilled from the reaction flask in vacuo. By mea s or th s procedure but substituting the 2- In this manner, the compounds listed below are pre- (oxoalkyl) derivatives of Preparation F wherein Y O d; and S for the 2-acetonyl substituted heterocyclic compounds used herein, the corresponding 2-heterocyclic f substituted 3-lower alkyl quinoxaline-l,4-dioxides are x produced. JA

A R, A 1

(CH2)4 H (CH CH, -(CH H (CH:):- n- C H, -(CH2)2 z s (CH2)5 z s -(CH2)2 l'1C H-, CH2C(CH;,),- H 2)2- |C.1H7 -CH CH(C H H (C z)z-" I1C4HQ -CH2CH(C2H5) CH3) (CH2)3- nC H -CH2CH(C2H- 5)'- a 1* (CH,)3 t-QH, CH(CH 1)CH- H -CH(CH3(CH(CH3 H CH2C(CH -,)2C- CH CH(CH3)CH(CH- CZH5* CH C(CH,-,) C- nC H a l:CH CH(CH )CH C- H )2CH,CH2CH(CH- CH3 cH cH cuncu cctm 3 T -CH2CH(CH3)CH2C- nC H CH C( H cm)( z it CH2C(CH3)(C2H5) 3" PREPARATION A Compounds of the formula 0 CH: K NJ *The N-substituted alkylenediamir es thus marked are prepared from the corresponding unsubstituted diamone by alkylation with the appropriate alkylbromide (R Br). The procedure comprises refluxing a mixture ofthe alkylenediamine (2.5-3.0 moles) with the appropriate alkylbromide (1.0 mole) for about six to eight hours. The mixture is then cooled, made alkaline and extracted with ether. The ether extracts are dried (K ICOM. the ether distilled off and the residue fractionated in vacuo to provide the N-substituted alkylenediarnine.

propriate alkanolamine (HOA--NH to about 5 C. to 200 C. until one molar equivalent of water is removed. The residue is then distilled in vacuo to give the cyclized compound. The following compounds are thus prepared:

PREPARATION C 2-Methyl-5,6-Dihydro-4H-1,3-Thiazine Thioacetamide (7.6 g., 0.1 mole) and 3- bromopropylamine hydrobromide (21.9 g., 0.1 mole) are thoroughly mixed and heated at 150 C. to C. for 15 to 20 minutes, then cooled and partitioned between ether and dilute aqueous hydrochloric acid. The aqueous phase is separated, cooled in an ice-bath and fresh ether added (100 ml.). The two phases are vigorously agitated and aqueous sodium hydroxide added until a pH of 10 to 11 is attained. The ether phase is separated, dried over anhydrous sodium sulfate and evaporated to provide the product which is fractionally distilled.

In this manner, the following compounds are prepared using the appropriate bromoor chloroalkylamine:

PREPARATION D The 2-methyl substituted cyclic thioamidates listed below are prepared by the procedure of Saulmann, Ber. 33, 2635 (1900). The procedure comprises refluxing thioacetamide (0.1 mole) with excess l molar) of the appropriate alkylene dichloride (Cl-ACl), or alkylene dibromide for about 8 hours or until elimination of the hydrogen halide ceases. The excess alkylene dihalide is then removed by distillation, the residue mixed with a large volume of water and heated. Hydrochloric acid is added to achieve solution of the residue. The solution is filtered, the filtrate neutralized with ammonium hydroxide and the product extracted with ether. The ethereal solution is dried (anhydrous sodium sulfate), decolorized, if necessary, and evaporated to give the product.

The following compounds are prepared in this manner:

PREPARATION E Ethyl-( 3-Methylquinoxaline-Z-Formimidate )-l ,4-

Dioxide Hydrochloride A solution of 2-cyano-3-methylquinoxaline-1,4- dioxide (0.1 mole) in dry ethanol (5.3 g., 0.12 mole) and dry ether (50 ml.) is saturated with dry hydrogen chloride while maintaining the temperature below 10 C. The mixture is then stirred overnight at room temperature under a dry nitrogen atmosphere. The solid is collected by filtration (ether is added to the reaction mixture, if necessary, prior to filtration) washed with ether and dried.

The following compounds are thus prepared:

N h o c2115 HCI \N/ -CHa C! cl-i Br OCH F CF PREPARATION F 2-Acetonylthiazoline To a solution of Z-methylthiazoline (4.95 g., 0.05 mole) in tetrahydrofuran (100 ml.) at 78 C. is added n-butyllithium (3.2 g., 0.05 mole) and the mixture stirred for 1 hour. Acetyl chloride (3.93 g., 0.05 mole) is then added dropwise to the mixture while holding the temperature below C. The mixture is stirred for 1 hour following completion of addition after which it vis allowed to warm to room temperature, then filtered.

The solvent is removed under reduced pressure and the residue distilled in vacuo to provide the product.

By means of this procedure, the 2-methyl substituted heterocyclic compounds of Preparations A, B, C and D re converted to the corresponding 2-(oxoalkyl)- derivatives of formula III wherein R is methyl, ethyl, n-propyl, n-butyl and isobutyl by substituting the appropriate alkanoic acid chloride (R COCI) for acetyl chloride PREPARATION G 2-Cyano-3-Lower Alkylquinoxaline-l ,4-Dioxides The general procedure comprises reacting the appropriate acylacetonitrile reactant (R CO-CH -CN) with an equimolar amount of the appropriate benzofuroxan reactant in methanol in the presence of an equimolar amount of sodium methoxide. The mixture is refluxed for 3 hours, the solvent removed under reduced pressure and the residue crystallized from a suitable solvent such as chloroform-methanol.

In this manner, the following compounds are prepared:

7 wherein X is selected from the group consisting of hydrogen, chloro, bromo, fluoro, methyl, methoxy and X trifluoromethyl;

R is selected from the group consisting of hydrogen and alkyl having one to four carbon atoms;

A is alkylene of from two to five carbon atoms which places at least two carbon atoms between the N X R2 x R2 atoms to which it is attached; F CH F n-C l'i, H i-C3H1 and the non-toxic acid addition salts thereof. CF CH3 OCH nC.-;H Cl iC H a E 2. A compound according to claim 1 wherein A is al- Br C l-i H nC H,, OCH i-C H1 kylene of from two to five carbon atoms which places F H gags S 2:??? two carbon atoms between the N atoms to which it is 85 3 2 CFa attached. CF3 1H5 H 4 B g1 nC 1 Cl 3. A compound according to claim 1 wherein X is What is claimed is: 1. A compound having the formula chloro, R is lower alkyl and A is (CH R is hydrogen and A is CH CH 5. A compound according to claim 2 wherein X is hy- 2 drogen, R is lower alkyl and A is CH CH 6. The compound of claim 3 wherein R is methyl.

7. The compound of claim 5 wherein R is methyl.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 8

DATED March 11, 1975 INVENTOR(S) Marwan J. Abu El-Haj It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 10, line 25, "-CH CH(i H should read CH CH(i-C H Col. 16, under PREPARATION B, the seventh entry under A (second occurrence) reading "-CH CH(C H )n-C H should read -CH CH(C H under PREPARATION B, the seventh entry under R (second occurrence) should read n-C H under PREPARATION B, the next to the last entry under A f'r t 0 rr e readin "CH C CH C H- 1 s ccu enc g 2 (C 3) 2 5) H II should read -CH C(CH (C H under PREPARATION B, the next to the last entry under R (first occurrence) should read H Signed and Sealed this twenty-sixth Day Of August1975 [SEAL] Attest:

RUTH c. MASON c. MARSHALL DANN Arresting Officer Commissioner of Parents and Trademarks 

1. A COMPOUND HAVING THE FORMULA
 1. A compound having the formula
 2. A compound according to claim 1 wherein A is alkylene of from two to five carbon atoms which places two carbon atoms between the N atoms to which it is attached.
 3. A compound according to claim 1 wherein X is chloro, R1 is lower alkyl and A is -(CH2)3-.
 4. The compound of claim 2 wherein X is hydrogen, R1 is hydrogen and A is -CH2CH2-.
 5. A compound according to claim 2 wherein X is hydrogen, R1 is lower alkyl and A is -CH2CH2-.
 6. The compound of claim 3 wherein R1 is methyl. 